Enantiomerically-enriched chiral primary amines are commonly used as resolving agents for racemic acids, as chiral auxiliaries for asymmetric syntheses, and as ligands for transition metal catalysts used in asymmetric catalysis. In addition, many pharmaceuticals contain chiral amine moieties. Effective methods for the preparation of such compounds are of great interest to the pharmaceutical industry. Particularly valuable are processes that allow for the preparation of each enantiomer or diastereomer in enantiomeric excess (ee) or diastereomeric excess (de), as appropriate, from prochiral or chiral starting materials.
As a result of the large number of chiral catalysts which are now commercially available, chiral amines can be easily obtained from the catalytic asymmetric hydrogenation of N-acyl enamines (enamides). The preparation of an enantiomerically-enriched amine via conversion of a precursor oxime to the corresponding enamide, which is subsequently converted to the amine through asymmetric hydrogenation and deprotection, has been described in WO 99/18065. The oxime-to-enamide conversion process of WO 99/18065 is, however, not of general applicability to a wide range of substrates. Moreover, many of the recognized processes require a large excess of metallic reagent to effect the conversion. For example, Burk et al. [J. Org. Chem., 1998, 63, 6084] reported that enamides could be prepared in 30-80% yield by heating the oxime in toluene at 70° C. in the presence of 3.0 eq. of acetic anhydride and 2.0 eq. of iron powder. However, this method is unsuitable for large scale manufacture because (a) it generates large amounts of iron waste, and (b) the initiation of the rapidly exothermic reaction is unpredictable. A different process, employing a phosphine as reducing agent, is disclosed in WO 2007/115185. The process of WO 2007/115185 is a workable process, upon which the instant process is an improvement.